Clinical Trial 23441

• Overview

  Study Title:

  Phase 1/1b Study of AKT Inhibitor Ipatasertib with Chemoradiation for Locally Advanced Head and Neck Cancer

  Objective:

  Primary Objectives: * To determine the MTD and recommended Phase 2 dose (RP2D) of ipatasertib in combination with definitive chemoradiation in locally advanced head and neck squamous cell carcinoma (HNSCC) based on dose-limiting toxicities (DLTs). Secondary Objectives: * To assess acute and late toxicities, based on CTCAE version 5.0. Toxicities occurring >90 days from the end of radiation therapy will be considered late toxicities. * To assess long-term swallowing function, based on gastric tube dependency at 6 and 12 months that is different from baseline. * To determine duration and completion rate of prescribed radiation and chemotherapy. * To determine pharmacokinetic profile of ipatasertib in combination with cisplatin and radiation therapy, based on peak and trough blood levels in patients administered ipatasertib orally. * To determine pharmacodynamic effects of ipatasertib at the MTD, based on pAKT, pS6 and pPRAS40 as markers of AKT pathway inhibition, and gamma-H2AX as a marker of radiosensitization. * To observe and record anti-tumor activity (objective response rate by RECIST criteria, locoregional control, relapse-free survival, and overall survival) of the combination of ipatasertib, cisplatin, and radiation therapy in patients with HNSCC. Although the clinical benefit of this combination has not yet been established, the intent of offering this treatment is to provide a possible therapeutic benefit, and thus the patient will be carefully monitored for tumor response and symptom relief in addition to safety and tolerability. * To correlate efficacy outcomes with tumor genotype, based on whole exome sequencing of pre-treatment biopsy specimens

• Treatments

  Therapies:

  Chemotherapy (NOS); Radiotherapy; Therapy (NOS)

  Medications:

  Ipatasertib (); cisplatin ()

• Inclusion Criteria

  Key Inclusion Criteria:
  • Patients must have pathologically confirmed HNSCC (including tumors of the oropharynx, hypopharynx, larynx, oral cavity, nasal cavity, maxillary and other paranasal sinuses, and unknown primary of the head and neck), with measurable disease as per RECIST 1.1.
  • Oropharyngeal and unknown primary squamous cell cancers must test for human papilloma virus (HPV), for example by p16 IHC, ISH, or PCR. HPV testing is not required for other HNSCC primary tumor sites.
  • Must be candidate for concurrent, definitive cisplatin and radiation therapy as judged by the treating physician.
  • Able to swallow tablets at the time of enrollment.
  • 18 years of age or older.
  • ECOG performance status 0-1.
  • Life expectancy of greater than 3 months.
  • Adequate organ and marrow function as defined within the protocol.
  • Human immunodeficiency virus (HIV)-infected patients are eligible if on effective antiretroviral therapy with undetectable viral load within 6 months.
  • Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as having a negative HBsAg test and a positive HBcAb test, accompanied by a negative HBV DNA test) are eligible. Patients with chronic HBV infection are eligible if the HBV viral load is undetectable on suppressive therapy, if indicated. Patients undergoing current treatment with anti-viral therapy for HBV are ineligible.
  • Patients with a history of hepatitis C virus (HCV) infection are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA. Patients with HCV infection who are currently on treatment are eligible if they have an undetectable HCV viral load.
  • Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.
  • The effects of ipatasertib on the developing human fetus are unknown. For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods with a failure rate less than 1% per year during the treatment period and for at least 28 days after the last dose of ipatasertib and agreement to refrain from donating eggs during this same period. For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm during the treatment period and for 28 days after the last dose of ipatasertib.
  • Ability to understand and the willingness to sign a written informed consent document.
  • For the expansion cohort only, patients must agree to undergo mandatory on-treatment biopsies, and have tumors amenable to on-treatment biopsies. This is not applicable to the dose escalation cohort where no on-treatment biopsies are obtained.
  • Other inclusion criteria may apply.

• Exclusion Criteria

  Key Exclusion Criteria:
  • Primary tumor of nasopharynx, salivary, thyroid or parathyroid glands, or skin.
  • Distant metastases from the current HNSCC.
  • Prior treatment (e.g. chemotherapy, radiation, or definitive surgery) for the current locally advanced HNSCC is not permitted. Biopsies, including those performed under anesthesia, are not considered surgery. Patients who underwent prior definitive surgery alone for an early stage (T1-2N0) HNSCC which has now recurred with Stage III-IVB disease at least 3 months after the initial surgery are eligible.
  • For patients with a prior history of another malignancy, no prior chemotherapy or radiation may have been administered within 6 weeks prior to study entry. Among patients who received prior radiation to the head and neck or adjacent anatomical site for another malignancy, there may be no overlap with current area to be irradiated.
  • Current use of any other investigational agents.
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to ipatasertib or other agents used in study.
  • Treatment with strong inhibitors or inducers of CYP3A4 or P-glycoprotein within 2 weeks or 5 drug-elimination half-lives, whichever is longer, prior to initiation of study drug. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently updated medical reference. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product. Appendix C should be presented to the patient.
  • Patients with uncontrolled intercurrent illness, including active infection.
  • Pregnant women are excluded from this study because ipatasertib is an oral AKT inhibitor with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with ipatasertib, breastfeeding should be discontinued if the mother is treated with ipatasertib. These potential risks may also apply to other agents used in this study.
  • Patients with Type I or Type II diabetes mellitus requiring insulin at study entry. Patients with non-insulin dependent Type II diabetes mellitus are eligible, as are patients who are on a stable dose of oral diabetes medication 4 or more weeks prior to initiation of study treatment. Patients with a history of Diabetes Mellitus, an abnormal fasting glucose level, or other signs or symptoms indicating Diabetes Mellitus, must meet the laboratory eligibility criteria for fasting blood glucose and hemoglobin A1c (see Section 3.1.9).
  • History of or active inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis) or active bowel inflammation (e.g., diverticulitis).
  • History of malabsorption syndrome or other condition that wousld interfere with enteral absorption or results in the inability or unwillingness to swallow pills.
  • Lung disease: pneumonitis, interstitial lung disease, idiopathic pulmonary fibrosis, cystic fibrosis, Aspergillosis, active tuberculosis, or history of opportunistic infections (pneumocystis pneumonia or cytomegalovirus pneumonia).
  • Known clinically significant history of liver disease consistent with Child-Pugh Class B or C, including active viral or other hepatitis (e.g., positive for hepatitis B surface antigen [HBsAg] or hepatitis C virus [HCV] antibody at screening), or cirrhosis. Refer to sections 3.1.11 and 3.1.12 for eligibility criteria for patients with a history of hepatitis B and C, respectively.
  • Other exclusion criteria may apply.

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